1,2,4-Triazol-3-one heterocyclic carbon compounds such as trazodone, etoperidone and nefazodone are known for their therapeutic use in treating depression. The pharmacological properties of trazodone has been published in several articles, see for example in Silvestrini, et al., International Journal of Neuropharmacology, 7 587-599 (1968) and those of etoperidone in P. Bertoletti, Clin. Med. 58,393 (1977).
Nefazodone and two processes for its preparation have) been described in Canadian Patent 1,198,436 and in PCT/EP93/03119 published May 26, 1994. The '436 patent relates to the preparation of 2-phenoxyalkyl-1,2,4 triazol-3-one derivatives Scheme 1 below depicts the two different methods described in the '436 patent. ##STR1## 5-Ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3-one, compound 1.3 is alkylated with 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine, compound 1.5 in the presence of base to give nefazodone. Alternatively, 2-3-4-(3-chlorophenyl)-1-piperazinyl!propyl-5-ethyl-4H-1,2,4-triazol-3-o ne, compound 1.4, is alkylated with 2-phenoxyethyl chloride in the presence of base to give nefazodone.
Canadian Patent, 1,233,826 relates to an improved process for obtaining the intermediate compound of Formula 1.3 in Scheme 1. PCT/EP93/03119 teaches another process for the preparation of triazolone compounds such as nefazadone and etoperidone wherein a carbonate derivative represented as compound 2.1 in Scheme 2 below is reacted with a N-substituted hydrazide of a carboxylic acid characterized by Formula 2.2. ##STR2##
It has now been found a novel process for the preparation of triazolone derivatives and in particular for the preparation of nefazodone.
When compared to the processes of the prior art, the applicant's invention introduces a number of advantages:
First, nefazodone is produced in considerably higher yields than the process taught by the prior art.
Second, it can easily be accommodated to industrial scale production. Nefazodone is produced in four steps from commercially available starting materials.
Third, the process of the present invention introduces the substituent at the position five of 2,4-disubstituted 1,2,4-triazol-3-one at the last step of the synthesis. This synthetic pathway allows for the manufacture of various 2,4-disubstituted 1,2,4-triazol-3-one bearing a different substituent at the position five of the ring. This flexibility is extremely interesting for the synthesis of other potential antidepressant agents.
Accordingly, one object of the present invention is to provide novel process for the production of nefazodone from readily available, inexpensive and relatively safe starting material. Other objects of this invention can be recognized by those skill in the art from the summary of invention and detailed description of embodiments thereof.